Chromosome and gene alterations in breast cancer as markers for diagnosis and prognosis as well as pathogenetic targets for therapy

Chromosomal abnormalities have been implicated in cancer development since the turn of the last century. Only during the past two decades, with advances in cytogenetics and molecular biology, has the genetic basis of neoplasia been firmly established, however, with chromosomal alterations being recognized as critical in the pathogenesis of human cancer. Recurrent chromosomal alterations provide cytological and molecular markers for the diagnosis and prognosis of disease. They also facilitate the identification of genes that are important in carcinogenesis and, ultimately, may lead to the development of targeted therapy. In breast cancer, the most prevalent malignancy among females, substantial progress has been achieved in identifying genes located at sites of recurrent chromosomal alterations and in profiling gene expression through the application of powerful cytogenetic and functional genomic techniques. Characterization of the molecular pathologic characteristics and gene-expression profiles of breast cancer should provide new clinical tools for the accurate diagnosis and prediction of prognosis as well as new targets for the development of therapeutic agents.     

子宫平滑肌肉瘤组织学诊断现状

子宫平滑肌肉瘤的组织病理学诊断有时十分困难,造成这种困难的原因是目前尚无完全统一的组织学诊断标准,诊断的难点在于如何辨认和综合分析各项诊断参数,而且仅仅根据组织学所见也很难预测其生物学行为。2003《WHO乳腺与女性生殖器官肿瘤病理学与遗传学》一书中除了将子宫平滑肌肿瘤分为良性（平滑肌瘤）和恶性（平滑肌肉瘤）之外,还引入了不能确定恶性潜能的平滑肌肿瘤这一诊断,从而废除了传统的两分分类法,应该说这是一个较为重大的进展。     

Minimal uterine serous carcinoma: current concepts in diagnosis and prognosis

Uterine serous carcinoma (USC) is an aggressive type of endometrial cancer with a propensity to have extra-uterine spread at diagnosis, in some cases despite limited involvement of the uterus. Serous endometrial intra-epithelial carcinoma (EIC) is a recently recognised entity with the same cytological features and p53 mutations as USC, but it does not demonstrate stromal or myometrial invasion. In addition to representing the putative precursor to USC, the pure form of serous EIC may also be associated with extra-uterine tumour at the time of diagnosis and with risk for recurrence, spread, and eventual death from tumour. Current evidence indicates that serous EIC is a form of minimal USC with behaviour that is stage dependent, thereby necessitating complete surgical staging despite limited disease in the uterus. We review the diagnostic criteria for minimal USC, pitfalls in the differential diagnosis, and discuss a practical approach to evaluating biopsies, polypectomies, or hysterectomies containing minimal USC.     

Circulating prognosis markers in melanoma: proteomic profiling and clinical studies

Cutaneous melanoma is the most dangerous skin cancer because of its ability to metastasize. Several clinical factors (number of invaded lymph nodes and/or presence of distant metastases) and histopathology (depth of tumor and presence of ulceration) are available to the clinician for determining prognosis and suggesting appropriate therapeutic management. However, these factors are often insufficient, especially in early forms of melanoma. Much research has focused on the identification of effective prognostic markers in serum. The only serum marker, which has been incorporated into the current AJCC classification for clinical use is lactate dehydrogenase dosage, a historical marker, restricted to the prognosis of metastatic disease. The recent development of technologies for proteome analysis offers new perspectives in this field. This review summarizes the specific considerations for each of the proteomic techniques used to date and presents the results of recent clinical investigations conducted to identify prognostic biomarkers in the serum of melanoma patients.     

肿瘤标志物在乳腺癌诊断及预后中的应用

肿瘤标志物已广泛应用于乳腺癌的诊断及预后.本综述总结了肿瘤抗原15-3 (CA15-3)、人表皮生长因子受体2( HER2)、雌激素受体(ER)及黄体酮受体(PR)等经典乳腺癌标志物的临床应用现状及新兴乳腺癌生物标志的临床价值.多标志物的联合检测较单一标志物有更高的灵敏度及特异性,将成为今后乳腺癌标志物的临床应用趋势.     

少突胶质细胞瘤的分子遗传学、病理与临床预后分析

目的 探讨少突胶质细胞肿瘤遗传分子表型、病理和临床预后的关系。方法 对51例（对）少突胶质细胞肿瘤和外周血进行DNA的提取,变性梯度凝胶电泳（DGGE）和DNA测序检测抑癌基因TP53、PTEN／MMAC1和p18突变;多重PCR检测EGFR扩增、p16／CDKN2A和p18缺失;多因素分析预后和生存期。结果 26例少突胶质细胞瘤中TP53和p18突变各1例;未发现PTEN／MMAC1突变;19．2％EGFR扩增;27％p16／CDKN2A缺失。25例GBMO中TP53,p18和PTEN／MMAC1突变分别是24％、0和20％。44％EGFR扩增,48％p16／CDKN2A缺失。所有肿瘤均未见p18同源性缺失。结论 缺乏TP53和PTEN／MMAC1突变是少突胶质细胞肿瘤独特的分子特性。其恶化进展和生存期短与EGFR扩增密切相关。     

Estrogen and progesterone receptor expression in uterine and extrauterine leiomyosarcomas: an immunohistochemical study.

The authors have noted anecdotal cases of extrauterine leiomyosarcomas (LMS) with estrogen receptor (ER) and progester-one receptor (PR) immunoreactivity. However, there are few studies that have compared ER and PR immunoexpression in LMS of uterine and extrauterine origin. The authors obtained a representative formalin-fixed, paraffin-embedded tissue block from cases of uterine LMS (n = 15) and extrauterine LMS (n = 16) from the archives of the Cleveland Clinic Foundation and performed immunohistochemical staining for ER and PR. Staining was evaluated by 2 observers in a semiquantitative manner using the following scale: 0, no nuclear staining; 1+, 1 to 25% of nuclei stained; 2+, 26 to 50% of nuclei stained; 3+, 51 to 75% of nuclei stained; 4+, 76 to 100% of nuclei stained. The majority of uterine LMS stained for ER (13 of 15, 87%), PR (12 of 15, 80%), or both ER and PR (12 of 15, 80%), with most cases showing 3+ or 4+ positive staining. For the extrauterine LMS cases, staining for ER was seen in 4 of 16 cases (25%), staining for PR was observed in 2 of 16 cases (13%), and staining for both ER and PR was seen in 2 of 16 cases (13%). One extrauterine LMS showed 4+ coexpression of ER and PR, but the remaining extrauterine cases showed only 1+ ER and/or PR immunoreactivity. These data suggest that most uterine LMS coexpress ER and PR, and most extrauterine LMS do not stain for these antigens. However, a subset of extrauterine LMS are ER and/or PR immunoreactive. This raises the possibility that hormonal manipulation may be beneficial in the treatment of these therapeutically recalcitrant tumors.     

Comparative immunohistochemical and molecular analysis of uterine and extrauterine leiomyosarcomas.

Histologic criteria defining malignancy in smooth muscle tumors are currently site specific. This study was undertaken to determine whether, in leiomyosarcomas (LMS) occurring in different anatomic locations, there were differences in patterns of expression of molecules that have been demonstrated to be associated with biologically aggressive behavior in malignant neoplasms, and also to determine their diagnostic utility. Formalin-fixed paraffin-embedded tissue blocks were selected from 16 extrauterine leiomyosarcomas (EULMS), 14 cases of uterine leiomyosarcomas (ULMS) and from five cases each of uterine and extrauterine leiomyomas (LM). Utilizing immunohistochemical (ABC) techniques with antigen retrieval, we assessed serial sections of each tumor for immunoreactivity with Glut1, CD44s, bcl2, cyclin D1, and estrogen receptor. Molecular genotyping for detecting k-ras-2 point mutation, p53 gene loss, and mdm2 gene amplification was performed on microdissected tumor samples from the same histologic sections. All of the uterine and extrauterine LM were diffusely positive for CD44s, bcl2, and cyclin D1, and uniformly negative for Glut1. In contrast, 50% of the ULMS and 25% of EULMS were Glutl positive. Moreover, Glut1 positivity closely correlated with aggressive biologic behavior reflected by distant metastatic spread. Eighty-percent of LM and 70% of the ULMS were estrogen receptor positive, whereas only one retroperitoneal tumor had focal weak positivity. Over 80% of the extrauterine and 50% of the uterine sarcomas showed absence of CD44s immunoreactivity. Percentage of cyclin D1 immunoreactivity was independent of tumor grade and inversely proportional to the percent of bcl2 positivity. An LMS of the male breast contained k-ras-2 exon 1 point mutation (codon 12 aspartate substitution of glycine). P53 allelic imbalance was present in 29% of ULMS and 57% EULMS. Mdm2 amplification was present in three of six EULMS but not in ULMS. In addition to clinical staging, Glut1 positivity together with patterns of immunoreactivity of CD44 and bcl2 may be helpful in identifying aggressive smooth muscle tumors of the uterus and some EULMS. The presence of estrogen receptor staining may be helpful in identifying uterine versus nonuterine LMS. Although sample numbers are too small for definite conclusions, this study suggests that there are differences in glucose transport, expression of adhesion molecules, and estrogen receptors in ULMS and EULMS, which in part may be due to the estrogen dependency of the ULMS. P53 mutations and mdm2 amplifications appear to be more frequent in EULMS.     

LncRNA PCAT6: A potential biomarker for diagnosis and prognosis of bladder cancer

BackgroundMany potential biomarkers have been identified and studied for bladder cancer diagnosis. In this study, we investigated the role of a new biomarker, long noncoding RNA (lncRNA) PCAT6, in bladder cancer diagnosis and prognosis.Methods and resultsThe lncRNA PCAT6 expression profile of BC is analyzed using the Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) data. PCAT6 expression level in 106 pairs of BC tissues and adjacent normal tissues was detected and compared using qRT-PCR. Then, the association between PCAT6 expression and clinicopathologic indicators of BC was evaluated. Meanwhile, the prognostic value of PCAT6 was tested using Kaplan-Meier analysis. Additionally, loss-of-function assays were used to explore the effect of PCAT6 on the biological function of BC cells.We identified that the expression level of PCAT6 in BC tissue was higher than that in adjacent normal tissues. And the BC patients have higher serum PCAT6 than that in healthy volunteers. In addition, the expression level of PCAT6 was correlated with tumor size (p = 0.005), differentiation (p = 0.018), TNM stage (p = 0.04), lymph nodes metastasis (p = 0.019), and distant metastasis (p = 0.028). Kaplan-Meier analysis showed that BC patients with high PCAT6 expression had shorter overall survival (OS) and progression-free survival (PFS). The loss-of-function results revealed that the proliferation and viability of BC cells in PCAT6 knockdown groups decreased significantly, compared with the negative control groups.ConclusionOur results demonstrated that PCAT6 might be a potential biomarker for diagnosis and prognosis of BC.     

Genomic alterations in human breast carcinomas

All human chromosomes were screened in 52 human breast carcinomas for the occurrence of allele losses, in order to identify genomic alterations involved in initiation and progression of the disease. Loss of chromosome 22 alleles was detected in 6 out of 8 lobular carcinomas, while chromosome 17 losses were most frequent in ductal carcinomas. Furthermore, patients who developed advanced disease after many years of mild clinical course showed significantly higher frequencies of allele losses in their primary tumors, compared to patients with a persistently mild disease course. Finally, in one case, molecular examination suggested a translocation t(10;17) with coamplification of the ERBB2 oncogene and chromosome 10 sequences present in the two tumors from this patient, consistent with one of the tumors being a metastasis originating from a subclone of cells in the other tumor.     

Genomic alterations in tubular breast carcinomas

Tubular carcinoma of the breast is a well-differentiated variant of invasive ductal carcinoma and has been shown to have an exceptionally favorable prognosis, as manifested by a low incidence of lymph node metastases and an excellent overall survival. It is unknown whether this subtype represents an early step along the continuum of development to a more aggressive, poorly differentiated ductal cancer, or whether these cancers are destined to remain well differentiated with limited metastatic potential. We undertook an analysis of 18 pure tubular carcinomas of the breast using comparative genomic hybridization to evaluate the chromosomal changes in these tumors. An average of 3.6 chromosomal alterations of the genome were identified per case. The most frequent change involved loss of 16q (in 78% of tumors) and gain of 1q (in 50% of tumors). All but one case with 1q gain also exhibited a concomitant 16q loss. Other frequent changes involved 16p gain in 7 of 18 cases (39%) and distal 8p loss in 5 of 18 cases (28%). Comparison with known genomic alterations in a mixed group of invasive cancers shows tubular cancer to have fewer overall chromosomal changes per tumor (P <.01), higher frequency of 16q loss (P <.001), and lower frequency of 17p loss (P =.007). These results strongly suggest that tubular carcinomas are a genetically distinct group of breast cancers.     

Pathological assessment of pancreatic endocrine tumors for metastatic potential and clinical prognosis

The prognostic significance of several pathological factors (tumor size, mitotic index, Ki-67 labeling index, and vascular invasion) and expression of exocrine markers (CA19-9, CEA, AFP, and trypsin) in pancreatic endocrine tumors was studied. A total of 20 specimens of metastasizing (n=10) and non-metastasizing (n=10) tumors were subjected to histological and immunohistochemical examination. The metastasizing tumors showed significantly larger size, higher Ki-67 labeling index, increased number of mitotic cells, and more frequent vascular invasion in comparison with the non-metastasizing tumors. It was difficult to determine the effect of individual factors on clinical outcome because of slow disease progression in almost all cases. Numerous mitotic cells and widespread necrosis, however, were thought to indicate a poor prognosis, and tumors with these characteristics were regarded as high-grade malignant endocrine carcinomas. In one case, one-third of the tumor tissue comprised trypsin-positive cells, the outcome was comparatively poor, and the behavior of the tumor resembled that of mixed acinar-endocrine carcinoma. A simple multifactorial approach may be effective for the identification of tumors at increased risk of metastasis, but it remains difficult to determine clinical prognosis. It is essential to at least distinguish high-grade endocrine carcinomas from the more common endocrine tumors.     

Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors

Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers. In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas. Overexpression of growth factor receptors (EGF receptor, c-erbB2, c-erbB3, TGF receptor I–III), growth factors (EGF, TGF, TGF-1-3, aFGF, bFGF), adhesion molecules (ICAM-1, ELAM-1) and gene mutations (p53, K-ras, DCC, APC) are present in a significant number of these tumors. These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection.Abbreviations EGF Epidermal growth factor - ELAM Endothelial leukocyte adhesion molecule - aFGF Acidic fibroblast growth factor - bFGF Basic fibroblast growth factor - HER Human EGF-receptor - ICAM Intercellular adhesion molecule - TGF Transforming growth factor     

Genomic alterations in salivary gland carcinomas: an illustrated update

Since the publication of our review on genomic alterations in salivary gland tumours in Diagnostic Histopathology in 2020, there have been several major developments. In the United Kingdom, next generation sequencing (NGS) of several tumour types is now commissioned by the National Health Service (NHS) either by whole genome sequencing (WGS) of fresh tumours, or targeted NGS in formalin-fixed paraffin embedded (FFPE) tissue. The UK genomic test directory includes several key gene fusion tests in salivary tumours, including NTRK, MAML2, EWSR1 and MYB. These can aid the clinician not only in refining histopathological classification in challenging cases, but they also have important therapeutic implications for patients with recurrent disease or where standard-of-care management options have been exhausted. This review will provide a brief update, including newly described entities since the previous review (most notably microsecretory carcinoma), as well as illustrating the utility of genomic testing in salivary tumours using several recent examples from our clinical practice.     

Oligodendroglioma: diagnosis and prognosis

Oligodendrogliomas represent only 4% to 7% of intracranial gliomas, but accurate diagnosis of this neoplasm is important. They occur almost exclusively in the cerebral hemispheres and are most common in adults in middle life. Although classically associated with calcifications, these may be present in only 50% of cases. Special diagnostic techniques, including touch imprint preparations, electron microscopy, and immunohistochemistry can be useful in diagnosis. Grading systems correlating with prognosis have not been well established, but two recent careful clinical and pathologic studies have provided concrete and apparently valid criteria for grading. There is some evidence that radical surgical excision improves survival. Most patients receive postoperative radiation therapy. Prospective controlled therapeutic trials are lacking, however.     

乳腺癌预后相关免疫组化指标分析

目的 研究BRCA1、MMP-2、PTEN、CD44v6、nm23-H1、Cath-D在乳腺癌组织中的表达及生物学意义,筛选与预后有关的最佳因子组合。方法 采用免疫组化S-P法标记上述指标。结果 （1）乳腺癌组织中PTEN、BRCA1、nm23-H1蛋白表达明显降低,表达水平与复发、淋巴结转移呈负相关,与生存期呈正相关。（2）CD44v6、MMP-2、肿瘤间质内Cath-D的蛋白表达增高并与淋巴结转移、复发呈正相关。（3）BRCA1蛋白与nm23-Hl、PTEN蛋白表达呈正相关,与MMP-2表达呈负相关。MMP-2蛋白表达与CD44v6表达呈正相关。结论 乳腺癌组织中MMP-2表达增强、nm23-H1和BRCA1表达抑制,可能作为预测肿瘤转移及判断预后的可靠指标。